NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu) AND Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Germline classification:: Pathogenic/Likely pathogenic (17 submissions)
Last evaluated:: Aug 15, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012934.33

Allele description [Variation Report for NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu)]

NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu)

Genes:

LOC106780800:CYP21A2 recombination region [Gene]
CYP21A2:cytochrome P450 family 21 subfamily A member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.33

Genomic location:

Preferred name:

NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu)

Other names:

V281L; CYP21A2*15

HGVS:

NC_000006.12:g.32040110G>T
NG_007941.3:g.6806G>T
NG_008337.2:g.74265C>A
NG_045215.1:g.2339G>T
NM_000500.9:c.844G>TMANE SELECT
NM_001128590.4:c.754G>T
NM_001368143.2:c.439G>T
NM_001368144.2:c.439G>T
NP_000491.4:p.Val282Leu
NP_001122062.3:p.Val252Leu
NP_001355072.1:p.Val147Leu
NP_001355073.1:p.Val147Leu
LRG_829t1:c.844G>T
LRG_829:g.6806G>T
LRG_829p1:p.Val282Leu
NC_000006.11:g.32007887G>T
NM_000500.5:c.844G>T
NM_000500.7:c.844G>T
p.Val282Leu

Protein change:

V147L; VAL281LEU

Links:

OMIM: 613815.0002; OMIM: 613815.0033; dbSNP: rs6471

NCBI 1000 Genomes Browser:

rs6471

Molecular consequence:

NM_000500.9:c.844G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.754G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.439G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.439G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Synonyms:: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency; CYP21 deficiency; 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
Identifiers:: MONDO: MONDO:0008728; MedGen: C2936858; Orphanet: 90794; OMIM: 201910

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033175	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1998)	germline	literature only	PubMed (7) [See all records that cite these PMIDs] 3260007, 2788081, 1985465, 1496017, 7635470, 8081391, 9661649
SCV000086803	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000245595	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Oct 17, 2014)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23359698, 23359706, 21609351, 20661889, 24033266
SCV000494239	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 27, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000611260	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000680185	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Oct 26, 2017)	maternal	clinical testing	Citation Link,
SCV001137080	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001142354	Reproductive Health Research and Development, BGI Genomics	no assertion criteria provided	Pathogenic (Jan 6, 2020)	germline	curation
SCV001193785	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 26, 2019)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20661889, 14513879, 23359698, 20926536, 1644925, 1864962, 2249999 Citation Link,
SCV002061154	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 2788081, 3260007, 1496017, 7635470, 1985465, 9661649, 8081391, 25356970, 20301350, 23359698, 30968594, 29996815, 26804566, 26206692, 27041116, 25741868
SCV002521256	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21609351, 10720040, 20661889, 25741868
SCV002769514	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23359698, 25741868
SCV003852661	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31344365, 25741868
SCV004041737	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Oct 9, 2023)	germline	clinical testing
SCV004806938	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005051737	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV005200514	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	1	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	not provided	2	2	not provided	not provided	not provided	literature only, clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Latino	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia.

Haider S, Islam B, D'Atri V, Sgobba M, Poojari C, Sun L, Yuen T, Zaidi M, New MI.

Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2605-10. doi: 10.1073/pnas.1221133110. Epub 2013 Jan 28.

PubMed [citation]

PMID:: 23359706
PMCID:: PMC3574933

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (27)

Details of each submission

From OMIM, SCV000033175.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (7)

Description

In 9 patients with nonclassic 21-hydroxylase deficiency (201910) associated with HLA-B14;DR1, Speiser et al. (1988) found a change in codon 281 from GTG, encoding valine, to TTG, encoding leucine. Speiser et al. (1989) concluded that this codon 281 mutation is a consistent change in nonclassic 21-hydroxylase deficiency associated with HLA-B14;DR1. The val281-to-leu mutation (V281L), found in association with the HLA-B14;DR1 haplotype, accounts for 75 to 80% of nonclassic 21-hydroxylase deficiency (Mornet et al., 1991). This mutation was observed in several patients by Wedell et al. (1992), who referred to it as VAL282LEU.

In an analysis of steroid 21-hydroxylase gene mutations in the Spanish population, Ezquieta et al. (1995) found that the most frequent mutation causing the late onset form of disease (present in 15 of 38 patients) was val281 to leu, found in 18 of 30 chromosomes (37%). This mutation is found in 34% of all cases of the nonclassic type (White et al., 1994).

In samples from 2 patients (1 with a cortisol-producing adenoma and 1 with an androgen-secreting adrenocortical carcinoma), Beuschlein et al. (1998) detected the heterozygous germline mutation val281 to leu in exon 7.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000086803.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000245595.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Val282Leu variant (NM_000500.7 c.844G>T) (also referred to as p.Val281Leu in the literature) in CYP21A2 is a well-established pathogenic variant and has b een reported in numerous individuals with non-classical congenital adrenal hyper plasia (CAH) (Marino 2001, Ezquieta 2010, New 2013). This variant has also been reported in ClinVar (Variation ID#12151), as pathogenic. This variant has been i dentified in 2.0% (175/8588) of Ashkenazi Jewish chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs6471), althou gh data at this locus may not be reliable due to high homology with a pseudogene . In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (Tusie-Luna 1990, Barbaro 2015). In summary, this variant meets our criteria to be classified as pathogenic for non-classical CAH in an autosom al recessive manner based on observations in individuals with this disease and f unctional evidence. ACMG/AMP Criteria applied: PM3 (upgraded to strong based on multiple occurrences), PS3, PP5 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000494239.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The well-known c.844G>T (p.Val282Leu) missense variant is frequently observed in individuals affected with non-classical congenital adrenal hyperplasia (GeneReviews: Nimkarn et al., 2016, , Eziquieta et al. 2010, Stikkelbroeck et al. 2003, Skordis et al. 2015, Ramazani et al. 2008). New et al. (2013) reported that 98% (n = 497) of individuals with Non-classical CAH harbored this variant and its frequency was very high in affected individuals from the Ashkenazi Jewish population. Although this variant is associated with non-classical CAH, individuals with classical CAH were also found to have this variant (New et al. 2013). Functional studies found that co-expression of this mutant protein and wild-type (WT) protein results in a dominant negative effect on the enzymatic activity of WT protein (Felix-Lopez et al. 2003). Other studies indicate reduced enzyme activity with the p.Val281Leu allele (Wu and Chung 1991, Haider et al. 2013). The variant is observed in the population databases at a frequency below expected for the carrier rate based on prevalence of disease (ExAC, 1000 Genomes, ESP). Reputable clinical labs have interpreted this variant as pathogenic (Partners HealthCare and Ambry Genetics). In summary, this mutation meets the criteria for a Pathogenic variant for Adrenal hyperplasia, congenital, due to 21 â€“ hydroxylase deficiency. We have confirmed this finding in our laboratory using Sanger sequencing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000611260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	1	blood	not provided		1	not provided	not provided	not provided

From Mendelics, SCV001137080.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Reproductive Health Research and Development, BGI Genomics, SCV001142354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_000500.7:c.844G>T in the CYP21A2 gene has an allele frequency of 0.023 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Val282Leu variant (NM_000500.7 c.844G>T) (also referred to as p.Val281Leu in the literature) in CYP21A2 is a well-established pathogenic variant and has been reported in numerous individuals with congenital adrenal hyperplasia (CAH), in trans with another pathogenic variant (PMID: 21609351; 20661889; 23359698). In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (PMID: 24953648). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193785.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

NM_000500.7(CYP21A2):c.844G>T(V282L, aka V281L) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the non-classic form of the disease. Sources cited for classification include the following: PMID 20661889, 14513879, 23359698, 20926536, 1644925, 1864962 and 2249999. Classification of NM_000500.7(CYP21A2):c.844G>T(V282L, aka V281L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From DASA, SCV002061154.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (16)

Description

The c.844G>T;p.(Val282Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12151; OMIM: 613815.0002; OMIM: 613815.0033; PMID: 20301350; 2788081; 3260007; 1496017; 7635470; 1985465; 9661649; 8081391;25356970; 20301350; 23359698) - PS4. Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(ClinVar ID: 65610, PMID: 20301350) - PS1. The p.(Val282Leu) was detected in trans with a pathogenic variant (PMID: 23359698; 24953648; 25041270; 20301350; 28359061) - PM3_strong. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From 3billion, SCV002521256.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The variant is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.552%. However, frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:20661889, 21609351). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.31; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012151). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:20661889, 21609351). A different missense change at the same codon (p.Val282Gly) has been reported to be associated with CYP21A2 related disorder (PMID: 10720040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769514.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM #201910) and hyperandrogenism nonclassic type, due to 21-hydroxylase deficiency (MIM #201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1504 heterozygotes, 2 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Val282Met): 3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated p450 domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories and has been reported in more than 500 patients, the majority of whom presented with non-classical congenital adrenal hyperplasia (ClinVar; PMID: 23359698). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003852661.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Heterozygous Missense variant c.844G>T in Exon 7 of the CYP21A2 gene that results in the amino acid substitution p.Val282Leu was identified. The observed variant has a minor allele frequency of 0.00528/0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 12151). Experimental studies have shown that this missense change affects CYP21A2 function (Karlsson L et al., 2019). This variant is frequently observed in individuals affected with non-classical congenital adrenal hyperplasia. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004041737.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806938.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051737.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili, SCV005200514.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Latino	1	not provided	not provided	clinical testing	PubMed (1)

Description

Combined evidence strength is Very Strong (score = 9): ClinVar classifies this variant as Pathogenic, 2 stars. backed by functional studies (PS3). Combined evidence strength is Very Strong (score = 9).Very Strong: Saphetor curators have classified this variant as Pathogenic.Supporting: LOVD classifies this variant as Pathogeni (PP5). Equivalent variant chr6:32040110 G>C (Val282Leu) is classified Pathogenic by UniProt Variants (PS1).UniProt protein CP21A_HUMAN Mutagen sequence annotations V > T: Decreased 21-hydroxylase activity. which qualifies as strong pathogenic (PM1). MetaRNN = 0.00966 is between 0.00692 and 0.108 = strong benign. Reducing to strength Supporting in view of the clinical evidence reported in PP5_Very Strong.We observed this variant in a 21-year-old patient with Turner syndrome and congenital adrenal hyperplasia.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

Relating variation to medicine